[unreadable] Lentiviral vectors are potent vehicles for gene delivery. RNAi has recently emerged as a novel, evolutionarily conserved pathway by which specific genes can be down regulated. We are currently working in the development of lentiviral vectors carrying poll promoters capable of driving the expression of small interfering RNAs (siRNAs); we have successfully achieved specific and stable down regulation of a number of genes both in vitro and in vivo using such vectors. Huntington's disease (HD) is an inherited neurodegenerative disease caused by a gain of function CAG triplet repeat expansion in exon 1 of huntingtin, a gene of uncertain function. We propose to develop lentiviral mediated siRNAs against huntingtin and characterize the vectors in vitro and in vivo. In particular we will seek in vivo proof of principle that disease progression in a transgenic mouse model of HD can be halted or retarded by this approach. We will do this monitoring disease progression after a) direct injection of lentiviral siRNA vectors into the brain and b) generating a double transgenic mouse with both the huntingtin transgene and an anti-huntingtin lentiviral silencing cassette. [unreadable] [unreadable]